Spatial orientation depends on the integrity of multiple neural systems. Acute or chronic neurological conditions that disrupt any of these systems can produce profound impairments in an individual's ability to remain spatially oriented within an environment. The lack of an effective treatment for Topographical Disorientation (TD), in combination with an aging population in which a growing number of individuals will be at risk for sustaining a stroke or developing AD, presents serious challenges for society in the management of these patients. Developing a treatment for TD will depend on the identification of an appropriate animal model of spatial orientation and the application of this model to investigate the contribution of specific neurotransmitter systems to spatial orientation. Previous work examining the neural basis of spatial orientation has focused on the use of navigational strategies that depend on landmarks in the environment; however, humans also use navigational strategies that are independent of environmental landmarks. The choice of navigational strategy depends on cue availability and environmental familiarity. The experiments outlined in this proposal continue a research program investigating the neural basis of spatial orientation The following goals were developed to establish the role of the cholinergic system in spatial orientation: 1) investigate the ability of the rodent model to dissociate the effects of cholinergic deafferentation of the hippocampus and cortex on spatial orientation, 2) examine the effectiveness of cholinergic treatments on restoring spatial orientation, 3) investigate the role of intact brain structures in mediating the recovered spatial orientation observed subsequent to cholinergic treatments. Establishing that cholinergic deafferentation fractionates the navigational strategies that are critical for spatial orientation reflects a novel framework for understanding TD. These studies will advance our understanding of the neural basis of spatial orientation, and the results may have implications for developing treatments for TD. [unreadable] [unreadable]